GLP-1 receptor agonists’ impact on cardio-renal outcomes and mortality in T2D with acute kidney disease

Previous studies have explored the effects of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in reducing cardiovascular events in type 2 diabetes. Here we show that GLP-1 RAs are associated with lower risks of mortality, major cardiovascular events (MACEs), and major adverse kidney events (MAKEs) in type 2 diabetes patients with acute kidney disease (AKD). Utilizing global data from the TriNetX database (2002/09/01-2022/12/01) and propensity score matching, we compare 7511 GLP-1 RAs users to non-users among 165,860 AKD patients. The most common causes of AKI are sepsis (55.2%) and cardiorenal syndrome (34.2%). After a median follow-up of 2.3 years, GLP-1 RAs users exhibit reduced risks of mortality (adjusted hazard ratio [aHR]: 0.57), MACEs (aHR: 0.88), and MAKEs (aHR: 0.73). External validation in a multicenter dataset of 1245 type 2 diabetes patients with AKD supports the favorable outcomes. These results emphasize the potential of GLP-1 RAs in individualized treatment for this population.

3. Abstract: Please include the main causes of AKI in this study (e.g.55.2% due to sepsis, 34.2% due to cardiorenal syndrome).4. Methods/Discussion: Please indicate which GLP-1RA's were used in this study, and which were classified as short-acting and long-acting compounds.In the discussion, please elaborate specifically how the pharmacokinetic profiles of these compounds may result in differences in pharmacodynamic effects in type 2 diabetes patients (i.e.tachyphylaxis).
Please add that there was a renal benefit of the short-acting GLP-1RA lixisenatide in ELIXA (Muskiet, Lancet DE 2018, PMID: 30292589) 5. Methods (Page 9; prespecified outcomes): Was mortality in the MAKE and MACE defined as all-cause mortality, or death due to renal and cardiovascular disease respectively?6. Methods (Page 10, Study Cohort, Line 158): Please rephrase the definition of the index date; it seems it was 90 days following hospital discharge; this marks an important factor of the study.7. Results (Page 17): Do the authors have an explanation why the negative outcomes all seem to be numerically higher in the GLP-1RA group, with some even almost reaching significance?Note that Crohn's disease is spelled incorrectly in the text and supplementary table.
8. Discussion (Page 21, line 338): Please show data that indicate that GLP-1RA's reduce hyperfiltration, as this -as far as I´m aware-has not been shown in eGFR trajectories of large outcome trials (while it is seen in those studying SGLT2 inhibitors), and specific mechanistic studies in humans did not find a beneficial effect of these drugs on measured (intra)renal hemodynamics.
they suggest a link between GLP-1 RAs treatment and kidney protecfion, especially for type 2 diabetes pafients with CKD [1]." Specifically, we have included "eGFR < 15 ml/min/1.73m 2 " as part of the criteria for MAKEs.Consequently, AKD pafients with baseline kidney funcfion less than 15 ml/min/1.73m 2 have been excluded from the analysis.Moreover, in contrast to the previous study where cardiogenic shock was included in the criteria for MACEs, this invesfigafion has replaced it with cardiogenic arrest to befter align with the outcomes observed in previous studies of GLP-1 receptor agonists [1][2][3].These adjustments aim to improve the specificity and clinical relevance of our findings regarding the effects of GLP-1 RAs.
We have revised the pafient enrollment algorithm in the Figure 1 for clarificafion and also revised the citafion regarding the descripfion of the TriNetX plafform to accurately acknowledge its source [4].This acknowledgment is essenfial to ensure transparency and to alleviate any concerns regarding the intenfion to conceal informafion.[Reference] Response: Thanks for your comment regarding the different pafient numbers between our current study and Ref. 20, the variafion can be primarily aftributed to the inclusion of a four-point MAKE criterion, which introduces "eGFR < 15 ml/min/1.73m 2 " as a qualifying event.The inclusion of this addifional criterion resulted in the exclusion of pafients who would otherwise qualify for the cohort under the three-point MAKE definifion used in Ref. 20.This exclusion is significant as pafients with an eGFR < 15 are more likely to be undergoing dialysis due to CKD progression, rather than as a direct result of an AKI event.

Revised
We believe that the use of a four-point MAKE, including "eGFR < 15 ml/min/1.73m 2 " offers a more precise tool for evaluafing the impact of GLP-1 RAs on kidney funcfion, parficularly in the context of AKI.This disfincfion is crucial because pafients with advanced CKD are typically managed differently, and their inclusion could potenfially confound outcomes related to AKI events.Removing pafients with eGFR < 15 ml/min/1.73m 2 can allow for a more focused study on AKI, as many of these pafients requiring RRT are due to CKD progression rather than AKI.
By focusing on pafients less likely to be affected by CKD progression, we can more accurately assess the relafionship between GLP-1 RA use and kidney-related outcomes post-AKI.
Therefore, while the cohort in the present study is smaller, the design offers a more targeted approach to understand the potenfial benefits and risks of GLP-1 RAs in a populafion that is more homogeneously impacted by AKI.This nuanced approach enhances the study's validity by ensuring that the observed outcomes are more likely aftributable to the effects of the intervenfion rather than the underlying chronic disease progression.
To further clarify this point, we have revised the pafient enrollment algorithm in the Figure 1 and exclusion criteria in the "Method" secfion (P.10).ensuring transparency and consistency in our approach.properfies, could be more effecfively manifested in such a populafion, resulfing in the more pronounced mortality risk reducfion seen in our study.We have added the comparisons in supplementary results (Suppl p.10).
Line 364: The authors focus on the many limitafions of the present study, some of them seems unnecessary.In general, the Discussion appear too long and should be restricted.
Response: Thanks for your comment.We have revised and shortened the limitafion part in the "Discussion" secfion (P.25-26).
Line 393: The conclusion must be less enthusiasfic.It must also be stressed that the results are hypothesis-generafing and must be validated in specific intervenfion trials.
Response: Thank you for your valuable suggesfion.We have revised the tone in line with your request in the "Discussion" secfion but also our conclusion (P.26), ensuring a more neutral expression regarding limitafions.
"These findings provide insight into the potenfial benefits of GLP-1 RAs, but they are preliminary and warrant further invesfigafion.Randomized Although the manuscript and results are of high clinical interest, some crifical comments and suggesfions may help the authors to improve the manuscript.
MAJOR comments: 1.The observafional design of this study requires that both cohorts are idenfical at the start to ascertain reliable clinical interpretafion of the results.This remains somewhat problemafic in the current study, despite the rigorous matching efforts by the invesfigators.The propensity score matching was performed using 25 variables, even including covariates 1 year before the index date.However, important factors that may differ between the cohorts from a clinical perspecfive were not sufficiently included/taken into account, most notably 1) HbA1c [before, at, and after the index date], 2) eGFR [before and at the index date; preferably an eGFR slope is needed BEFORE the AKI event took place], 3) presumpfive causes of AKI.Please clarify why this was not taken into account, amend if possible, and include a detailed discussion how this (likely) affected the outcomes.Please show HbA1c and eGFR before, at and following the index date (crude numbers; not percentages), using as many fimepoints available.A higher HbA1c before the index date may result in increased CV and renal risk (legacy effect), a steeper eGFR slope before the index date may result in an earlies renal event at follow-up; a single fimepoint does not cover the full risk of an individual pafient or cohort; this issue should be discussed in the limitafion secfion.Why did the authors not match for presumpfive cause of AKI, as this may influence recurrence or other outcomes of interest.

Response:
We appreciate your insighfful comments and have conducted a thorough review of our data, focusing parficularly on the HbA1c and eGFR metrics as well as presumpfive causes of AKI.
Upon further analysis, our inifial observafions did not show significant stafisfical differences between the two groups in the study period (HbA1c p-value = 0.2556, eGFR p-value = 0.818).However, our repeated evaluafions revealed that, throughout the AKD, HbA1C levels were consistently higher in the GLP-1 RAs group compared to the control group, indicafing that the reduced risk of adverse outcomes associated with GLP-1 RAs is not mainly aftributable to the "legacy effect." Addifionally, the sustained difference in HbA1C levels between the GLP-1 RAs group and the control group prompts us to consider the role of pleiotropic effect addifional to glycemic control in the cardiovascular risk reducfion observed with GLP-1 RAs therapy, as suggested in the literature [1].
In terms of kidney funcfion, while the inifial eGFR readings were We acknowledge the importance of considering the influence of presumpfive AKI causes on the study's outcomes.In response to your concerns, we have conducted a series of sensifivity analyses to address this issue in the supplement file (Table S7).Our results confirmed the robustness of our primary results.This crucial step reinforces the validity of our findings, affirming that the observed benefits of GLP-1 RAs were not confounded by the inifial reasons for renal injury.
We have revised the "Result" and "Discussion" secfion in our manuscript (P.15, P.17, P. 20, and P. 22) and added two new suppl figures (Figure S1 and S2) to provide an in-depth explorafion of the various factors impacfing our cohort's results.Response: Thank you for your inquiry regarding the rafionale behind our selecfion of covariates for the Cox regression models.The selected covariates were as outlined in Table 1, which are wellestablished risk factors for cardiovascular and renal outcomes in diabetes, and their inclusion is intended to provide a comprehensive assessment of these risk factors on the outcomes.
We appreciate the astuteness of your query regarding the inclusion of covariates such as HbA1c, blood pressure, lipids, and BMI in our Cox regression models.These variables, recognized for their strong associafion with cardiovascular and renal outcomes in pafients with diabetes, were indeed incorporated to mifigate potenfial confounding effects (table 1).By including these factors, we aimed to refine our models and underscore the independent associafion between GLP-1 RAs use and the targeted outcomes.Your insighfful inquiry has reinforced the robustness of our analysis (please see table 1) In response to the second aspect of your query, we recognize the significance of assessing HbA1c levels between groups treated with GLP-1 RAs and other acfive glucose-lowering therapies during the follow-up period.Our detailed analysis indicates that HbA1c levels were consistently higher in the GLP-1 receptor agonist group compared to the group receiving other glucose-lowering treatments.This observafion suggests that the decreased risk of adverse outcomes in the GLP-1 RAs group may not be directly related to improved glycemic control.Instead, it points towards the broader mulfifaceted benefits of GLP-1 receptor agonists in addifion to glycemic control.
We have revised the "Method" and "Result" secfion in our manuscript (P.12 and P.18) and added a new suppl figure (Figure S3) to address your comments.Perhaps the authors should call for studies that in line with these studies invesfigate the benefit of GLP-1 during dialysis on outcomes?
Response: We thank you for your insighfful observafions regarding the rapid divergence observed in the Kaplan Meier curves for mortality, MACE, and MAKE, and the suggesfion to explore alternafive or addifional explanafions for the benefits of GLP-1 RAs therapy in our study populafion.
Thank you to point out that the survival benefits of GLP- Addifionally, in the "Discussion" secfion of our manuscript, we have elaborated on the significant potenfial of GLP-1 RAs to improve outcomes related to sepsis as the leading cause of AKI from our cohort.This is parficularly relevant given the increased suscepfibility of pafients with diabetes and kidney impairment to sepsis and the associated poor We have revised our manuscript to include these discussions, providing a more comprehensive view of the potenfial mechanisms through which GLP-1 RAs might exert their benefits in the studied populafion (P.20-21, P.23-24).We also echo the call for further studies aimed at invesfigafing these mechanisms in detail, parficularly in the context of acute cardiac and renal events.
[Reference] 1.The period of our study, from 2002 to 2022, was marked by evolving clinical pracfices regarding GLP-1 RAs use in kidney impairment.We recognize that our inability to ascertain the specific reasons for GLP-1

Goodwill, A.G., et al. Cardiovascular and hemodynamic effects of
RAs therapy inifiafion precludes a definifive analysis of their indicafions in our AKD cohort.Most of them (49.6%) were ever users before index hospital discharge.In response, we've conducted sensifivity analyses focusing on pafients prescribed exendin-based GLP-1 RAs, acknowledging their contraindicafion in severe kidney dysfuncfion (eGFR < 30 ml/min/1.73m 2 as per the current clinical recommendafion) [1].
Although these analyses affirmed the consistency with the primary analysis, the limited number of pafients in this subgroup resulted in findings that were not stafisfically significant, as anficipated.
We appreciate the opportunity to delve deeper into the nuances of our data and believe that these addifional analyses enrich the overall findings of our study by clarifying the potenfial risks and benefits of GLP-1 RAs therapy, especially in the presence of renal challenges.In the revised manuscript, we've expanded the "Result" secfion, limitafion part in the "Discussion" secfion, and Supplementary file (P.17, P. 25-26, Suppl P.9, table S8 and S9) to highlight the lack of detailed prescribing rafionales and the potenfial for confounding by indicafion.In response to your concern, we agree that inifiafing the dataset analysis from a point prior to the availability of GLP-1 RAs could potenfially impact the interpretafion of our findings.To address this and ensure the robustness of our conclusions, we have conducted a sensifivity analysis by adjusfing the start point of our dataset from Jan 2006 to Dec 2022.This adjustment allows for a period of GLP-1 RAs establishment in clinical pracfice, thereby ensuring that the pafients included in our study could have had access to these medicafions.
The results from this sensifivity analysis were consistent with our original findings, indicafing that the observed associafions between GLP-1 RAs use and the outcomes of interest are not arfifacts of the dataset's inifial fime frame.We believe this strengthens the validity of our conclusions and appreciate the opportunity to clarify this aspect of our methodology.
We have included the details of this sensifivity analysis in the revised Figure 3 and supplement appendix (Suppl.P. 9), ensuring that readers are aware of both the rafionale behind the original dataset fimeframe and the steps taken to validate our findings against potenfial temporal biases.

30292589)
Response: Thanks for your suggesfion.In our study, we included a range of GLP-1 RAs, both short-acfing and long-acfing.The short-acfing GLP-1 RAs used were exenafide and lixisenafide, and the long-acfing ones included liraglufide, dulaglufide and semaglufide.We have now added this informafion to the "Methods" secfion of our manuscript (P.11-12).
In the discussion, we have elaborated on how the differences in the pharmacokinefic profiles between short-acfing and long-acfing GLP-1 RAs can lead to varied pharmacodynamic effects.For instance, shortacfing compounds primarily affect postprandial glucose levels by slowing gastric emptying and inhibifing post-meal glucagon release, while longacfing compounds provide a more consistent sfimulafion of insulin release and suppression of glucagon, which can be beneficial in reducing fasfing glucose levels and may result in less tachyphylaxis over fime.We have also included the reference to the ELIXA trial (Muskiet, Lancet DE 2018, PMID: 30292589), which provides evidence of the kidney benefits of the short-acfing GLP-1 RAs lixisenafide.This trial's findings support the potenfial for differenfial effects of GLP-1 RAs based on their durafion of acfion, not only on glycemic control but also on kidney outcomes.We believe that these addifions will greatly enhance the discussion of our results, providing a more complete picture of how the pharmacokinefic properfies of GLP-1 RAs may lead to specific clinical benefits in pafients with type 2 diabetes and AKD.
We appreciate your valuable suggesfions and have incorporated these, especially lixisenafide in ELIXA into our manuscript accordingly (P.22-23).Due to the nature of our data collecfion, which relies on diagnosfic codes, we acknowledge that it is not feasible to precisely determine whether mortality was directly related to renal causes.This limitafion stems from the inherent restricfions of using diagnosfic codes for mortality aftribufion, which may not always allow for a clear disfincfion between renal-related and other causes of death.
We are grateful for your insightful comments and the opportunity to clarify this aspect of our study.We have revised the "Discussion section" (P.25), especially study limitation.Thank you once again for contributing to the improvement of our manuscript.Response: We sincerely appreciate your detailed examinafion of our manuscript and the valuable comments you have provided, especially regarding the observed results of negafive outcomes and the spelling error idenfified.
Regarding the negative outcomes observed in the GLP-1 RAs group, we have considered several potential explanations for the numerically higher incidence of negative outcomes compared to the control group.These include, but are not limited to, the baseline characteristics of the patient population, the inherent pharmacological effects of GLP-1 RAs, and possible unmeasured confounders that could influence the outcomes.It is important to note that our study was designed to explore associations rather than establish causality, and these findings suggest avenues for further investigation rather than definitive conclusions about the safety profile of GLP-1 RAs.
In our analysis, we adjusted for known confounders to the extent possible; however, as with any observational study, the potential for residual confounding exists.Additionally, the patient population receiving GLP-1 RAs may have had a higher baseline risk for certain adverse outcomes, which could not be fully accounted for in our analysis.It should be noted that despite the numerically higher incidence of negative outcomes in the GLP-1 RAs group, the overall prognosis may still be favorable in those treated with GLP-1 RAs.This observation could reflect the higher baseline risk for these outcomes among patients treated with GLP-1 RAs.
Thank you once again for your insightful feedback and for contributing to the improvement of our work.Response: Thank you for your valuable comments on the renoprotecfive effects of GLP-1 RAs.Recently, in individuals with type 2 diabetes and CKD, the FLOW trial indicates a decelerafion in CKD progression and a reducfion in kidney and CV mortality risk [1].
In our study, we noted a more gradual eGFR decline among users of GLP-1 RAs, which may hint at an influence on renal hemodynamics.The suggesfion that reducfions in glomerular hyperfiltrafion could serve as a renoprotecfive mechanism was informed by established hypotheses [2][3], yet it was not a direct finding from our research.
In response to your insights, we have revised our discussion for clarity.We now state more caufiously that our study suggests a potenfial mechanism involving the modulafion of renal hemodynamics by GLP-1 RAs, recognizing that this concept has not been definifively proven.
However, as a retrospecfive analysis in nature, we acknowledge and emphasize that our study does not provide direct evidence of changes in glomerular hyperfiltrafion, and we agree that the eGFR trends observed warrant further invesfigafion to uncover the precise underlying mechanisms.
We are grateful for the chance to refine our manuscript (P.21-22) to befter align with current scienfific knowledge and are eager to contribute to the ongoing dialogue on this important clinical topic.
[Reference] Thank you once again for your thorough considerafion of our study.
We firmly believe that the revisions made in response to the Reviewers' valuable feedback have significantly improved the clarity and quality of our research findings.We are hopeful that you will find our manuscript suitable for publicafion.
In addifion to addressing these suggesfions, we have also enlisted the assistance of one author to enhance our response to the queries: 1. Tao-Min Huang: Tao-Min Huang has been included as an author in this revision due to his significant contribufions to data analysis and data interpretafion, which have notably improved the overall quality of our research.His experfise in clinical nephrology has played a pivotal role in advancing our work.
We have confirmed that all authors have reviewed and agreed to these changes in authorship.We remain commifted to the accuracy and integrity of our manuscript.This addifion of author was made to further strengthen the research, and we appreciate your understanding of this change.

REVIEWERS' COMMENTS
Reviewer #1 (Remarks to the Author): I am fully satisfied about the revision.The authors did a good job.
are cleared by the kidneys, and in the light of the early years after GLP-1RA's were introduced (2005-2013) with case reports of acute kidney failure as a result of GLP-1RA use were published (e.g.Filippatos World J Diabetes 2013; PMID 24147203).MINOR comments: 1.The dataset spans a time period from September 2002 onward; what was the rationale for the 2002 timepoint in this study, as GLP-1RA's were not available until 2004/2005.2. Title (Page 1): Please include the outcomes investigated (ie.Cardio-Renal Outcomes and Morality), and that this is a Retrospective Observational Cohort study from the TriNetX Collaborative Network.
.M., et al.Effect of the glucagon-like pepfide-1 receptor agonists semaglufide and liraglufide on kidney outcomes in pafients with type 2 diabetes: pooled analysis of SUSTAIN 6 and LEADER.Circulafion 145, 575-585 (2022).Line 111: The authors quote Ref 20 for describing the TriNetX plafform.However, they apparently forgot to acknowledge that Ref. 20 is the brother paper of the present one in which they evaluated the effect of SGLT-2 inhibitors (another class of new anfi-hyperglycemic agents) within the same cohort.They must clearly acknowledge the paper in order to remove the suspicion they want to hide something.They also need to precise how and why the secondary outcomes (MACEs and MAKEs) in the present study are a liftle bit different from those of Ref. 20. Response: Thanks for your comment.We have addressed the concerns raised by adding a relevant secfion about the methodological divergence and outcome analysis between the current study and our previous SGLT-2 inhibitors study in the supplementary file (Suppl.P.10).In this study, adjustments have been made to the definifions and analyses of secondary outcomes compared to our prior invesfigafion ufilizing the TriNetX plafform to evaluate SGLT-2 inhibitors (as referenced in Ref. 20).
controlled trials are necessary to validate if GLP-1 RAs genuinely enhance the health of these pafients and to ensure their safety."Reviewer #2 (Remarks to the Author): This interesfing manuscript by Heng-Chih Pan et al. reports the results of a retrospecfive observafional real-world study in 165,860 pafients with type 2 diabetes that were admifted to healthcare facilifies with dialysisrequiring acute kidney injury.The invesfigators examined the long-term effects of GLP-1RA therapy versus no GLP-1RA therapy in this populafion, employing propensity score matching to create comparable groups, on all-cause mortality (primary outcome), and major adverse cardiovascular and kidney events (secondary outcomes, both defined as a 4-point composite) after a median follow-up of 2.3 years.The results implicate that GLP-1 RAs improves survival and cardiorenal outcomes in this populafion, after adjusfing for covariates, and remained consistent across subgroup and sensifivity analyses.

2 .
Please explain the rafionale for the covariates that were chosen in the cox regression models.Please add HbA1c, blood pressure, lipids, BMI to the cox-regression models, to gain understanding of the role of these risk factors in explaining the outcomes.If the outcome is explained to large extent by HbA1c, then the drug-specific benefit of GLP-1RA should be quesfioned.In line, in the light of the sensifivity analysis between GLP-1RA and other acfive glucose-lowering treatments, please include potenfial HbA1c differences between groups during the follow-up period.

outcomes[ 5 ]
. Our observafions, along with emerging evidence, suggest that increfin-based therapy could mifigate excessive inflammafion and microvascular thrombosis in sepsis through the acfivafion of the GLP-1 receptor, aligning with the findings by Chen et al. that GLP-1 RAs might offer protecfive benefits against sepsis-related mortality[6][7].This addifion underscores the mulfifaceted potenfial of GLP-1 RAs therapy beyond the tradifional metabolic benefits, potenfially offering a crucial advantage in managing sepsis outcomes in this vulnerable populafion.Given the rapid effects observed and the potenfial mechanisms discussed, we propose that future studies should explicitly invesfigate the short-term benefits of GLP-1 RAs therapy in populafions at risk of or recovering from AKI, including those undergoing dialysis.Such research would be invaluable in delineafing the acute versus chronic benefits of GLP-1 RAs and understanding the opfimal fiming and pafient populafion for these therapies.

Response:
We thank for your insighfful observafions on GLP-1 RAs prescripfions during AKD and the use of exendin-based GLP-1 RAs in pafients with kidney impairment.Conducfing our study with a retrospecfive healthcare database posed inherent limitafions, notably the lack of detailed clinical notes to precisely determine the indicafions for GLP-1 RAs inifiafion during AKD.This common challenge in database research is parficularly perfinent given the caufious clinical approach recommended for GLP-1 RAs use in pafients with kidney impairment.

MINOR comments: 1 .
The dataset spans a fime period from September 2002 onward; what was the rafionale for the 2002 fimepoint in this study, as GLP-1RA's were not available unfil 2004/2005.Response: Thank you for your insighfful observafion regarding the starfing point of our dataset in September 2002, especially in light of the fact that GLP-1 RAs were not introduced unfil April 2005[1].Your crifique is both valid and appreciated, as it highlights a crifical aspect of our study's design and its alignment with the fimeline of GLP-1 RA availability.

which have significantly contributed to enhancing the quality and rigor of our work. Revised Figure 3 .
Subgroup analysis.Forest plots of adjusted hazard ratios for the GLP-1 RAs users versus non-users during the AKD period regarding the long-term risks of sensitivity analysis for all-cause mortality, MACEs, and MAKEs.The hazard ratios were adjusted for age, sex, and race due to their potential interactions with kidney disease.Adjusted HRs and 95% CIs (error bars) are presented.The vertical line indicates an HR of 1.00; lower limits of 95% CIs with values greater than 1.00 indicate a significantly increased risk.

5 .
Methods (Page 9; prespecified outcomes): Was mortality in the MAKE and MACE defined as all-cause mortality, or death due to renal and cardiovascular disease respecfively?Response: Thank you for your thorough review and insighfful query regarding the mortality definifions in MAKE and MACE as described in our manuscript.To clarify, within the context of our study, MACE indeed encompasses mortality aftributed to cardiac death (ICD, I46), as explicitly stated in our text.However, your quesfion regarding the specificity of the mortality causes within the MAKE definifion highlights a significant methodological constraint in our research.

6 .
Methods (Page 10, Study Cohort, Line 158): Please rephrase the definifion of the index date; it seems it was 90 days following hospital discharge; this marks an important factor of the study.Response: Thank you for your valuable suggesfion, we have revised the sentences accordingly (P.10).7.Results (Page 17): Do the authors have an explanafion why thenegafive outcomes all seem to be numerically higher in the GLP-1RA group, with some even almost reaching significance?Note that Crohn's disease is spelled incorrectly in the text and supplementary table.
8. Discussion (Page 21, line 338): Please show data that indicate that GLP-1RA's reduce hyperfiltrafion, as this -as far as I´m aware-has not been shown in eGFR trajectories of large outcome trials (while it is seen in those studying SGLT2 inhibitors), and specific mechanisfic studies in humans did not find a beneficial effect of these drugs on measured (intra)renal hemodynamics.

Reviewer # 2 (
Remarks to the Author): I thank you for your time and effort to extensively address all queries raised in your robust point-by-point response.I believe the added analyses and your thorough revision of the manuscript greatly enhanced its scientific quality, balance and clinical relevance.I have no further comments.

Table S8 . Incidence of outcomes of interest among the GLP-1 RAs users compared to the control group after propensity score matching, in patients treated with Exenatide and an eGFR ≥ 30 ml/min/1.73m 2
Abbreviations: aHR, adjusted hazard ratio; MACE, MAKE, GLP-1 RAs; glucagonlike peptide 1 receptor agonists

Table S9 . Incidence of outcomes of interest among the GLP-1 RAs users compared to the control group after propensity score matching, in patients treated with Exenatide and an eGFR < 30 ml/min/1.73m 2
Muskiet, M.H.A., et al.GLP-1 and the kidney: from physiology to pharmacology and outcomes in diabetes.Nat Rev Nephrol 13, 605-628 (2017).